Disrupting the Senescence-Associated Secretory Phenotype–M1Macrophage Feedback Loop in Synovitis Using Dual Nano-Switches To Restore Joint Homeostasis

Osteoarthritis (OA), a leading cause of disability worldwide, impacts over 300 million people through progressive joint degeneration marked by chronic pain and functional impairment. A key driver of osteoarthritis progression is synovitis, characterized by inflamed synovial tissue harboring senescent fibroblasts and pro-inflammatory macrophages. These senescent cells secrete senescence-associated secretory phenotype (SASP) components, includining cytokines and proteases, which drive macrophage polarization toward a pro-inflammatory M1 state. Simultaneously, M1 macrophages release reactive oxygen species (ROS) and inflammatory mediators, amplifying cellular senescence and establishing a pathological feedback loop. Unfortunately, conventional single-target therapies, such as senolytics or macrophage modulators, fail to address this interdependence vicious cycle. Herein, guided by bioinformatics analysis integrated with clinical and murine specimen data, we developed an easy-to-produce combinatorial nanomedicine platform comprising: (i) synovium-targeting liposomes delivering senolytics to clear senescent fibroblasts and suppress SASP, and (ii) M2 macrophage-derived exosomes to convert M1 macrophages into regenerative M2 phenotypes. In rat OA models, this dual approach combined disrupted the senescence-inflammation cascade, achieving 73.53% synovitis index reduction and 75.00% OARSI score reduction. In summary, by concurrently clearing SASP-producing senescent cells and pro-inflammatory M1 macrophages, our strategy restores joint homeostasis and presents a translatable framework for treating age-related inflammatory disorders.